Propranolol: A “Heart Drug” that Stops Cancer Progression due to Stress

Background:

Propranolol is a drug commonly used to treat high blood pressure, irregular heart rhythms, pheochromocytoma (tumor on a small gland near the kidneys), certain types of tremor, and hypertrophic subaortic stenosis (a heart muscle disease). It is also used to prevent angina (chest pain), migraine headaches, and to improve survival after a heart attack.

Propranolol is in a class of medications called beta blockers. It works by relaxing blood vessels and slowing heart rate to improve blood flow and decrease blood pressure.

β-Adrenergic system in the human body has been suggested to be a backstage manipulator regulating tumour progression and drug target in cancer therapy (Ref.). In this context, Propranolol, a modulator of the β-Adrenergic system has been shown to lead to the cancer cells death in various tumor cells such as: pancreas, breast, ovary, colorectal, Oesophagus, Stomach, Lung, Prostate, Nasopharynx, Melanoma, Leukaemia, Hemangioma, Hemangioendotheliom, Angiosarcoma (Ref.).

Indeed, researchers looked back at patients who took Propranolol for blood pressure to see how they fared compared to the rest of the patients. Here are a few examples of such studies:

• • Beta-Blockers: Evidence of Mortality Benefit in Ovarian Cancer: http://www.medpagetoday.com/HematologyOncology/OvarianCancer/53298
    “The subgroup of patients treated with nonselective beta-blockers (e.g. Propranolol) had a median overall survival of 95 months versus 38 months for patients treated with beta-1 selective agents”

• • Effect of long-term propranolol treatment on hepatocellular carcinoma incidence in patients with viral C cirrhosis. (Ref.)
    “This retrospective long term observational study suggests that propranolol treatment may decrease HCC occurrence in patients with HCV cirrhosis.”

• Beta-blockers tied to breast cancer survival http://www.reuters.com/article/us-beta-blockers-idUSTRE74U6OD20110531
  “Women taking propranolol also fared better after being diagnosed with the disease: After five years, an estimated nine percent had died of breast cancer, compared to 27 percent of women not on propranolol.”

As suggested by academic research and demonstrated by various case reports there is an important anti cancer potential behind Propranolol. That, next to its safety profile, accessibility and low cost, makes this drug very attractive.

Here are a few article that may be nice to read on Propranolol anti cancer effect:

• Could a common and inexpensive heart medicine (beta-blockers) help cancer patients live longer?
• Cheap blood pressure drug ‘slashes breast cancer risk’
• Heart Drug Linked to Extra Years for Cancer Patients
• Conventional heart drug stops the progression of cancer
• BETA-BLOCKERS AS ANTI-METASTATIC DRUGS
• Stress fuels breast cancer metastasis to bone & Propranolol stops that

And here are articles related to other interesting effects related to the use of Propranolol

• Could a blood pressure drug dim bad memories?
• The Science of Stage Fright: How Stress Causes ‘Brain Freeze’

As it will be discussed below, essentially one of the major mechanism behind the anti cancer effect of Propranolol is the following:

• chronic stress (typical for cancer patients) triggers the production of  some substances (epinephrine/adrenaline, norepinephrine/noradrenaline and other hormons)
• these dock into some receptors that are located (also) on the cancer cells, called beta-adrenergic receptor, activating these receptors
• activation of these receptors triggers a chain of reactions that promotes cancer cell survival, mobility, invasion of neighboring tissue and creation of new blood vessels to supply the tumor
• if administrated to a patient, Propranolol will reduce or block the activation by norepinephrine and other hormones of this chain reaction, by inhibiting the beta-adrenergic receptors

Update November 8th, 2019: Here is a mechanism that explains even more clearly how Propranolol inhibits the chronic stress-induced cancer: Chronic stress triggers epinephrine release -> epinephrine release triggers activation of LDHA and thus enables fermentation (Ref.). In addition, chronic exposure to epinephrine promotes the establishment of immunosuppressive micro-environments through the induction of a COX2-dependent pathway (Ref.). Propranolol inhibits the activation of LDHA and COX2 via inhibition of the beta-adrenergic receptors. More on the anti cancer mechanisms related to Propranolol is discussed below.

Case reports or studies in humans:

• • Targeted therapy with propranolol and metronomic chemotherapy combination: sustained complete response of a relapsing metastatic angiosarcoma http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4303616/
    We report here a case of a 69-year-old woman with a relapsing metastatic angiosarcoma treated with a combination of metronomic chemotherapy and propranolol. The beta blockers were added since the tumour was positive for betaadrenergic receptor. A complete response was quickly obtained and lasted for 20 months. With this case, the combination of metronomic chemotherapy and propranolol in angiosarcoma warrants additional studies and illustrates the potential of metronomics to generate innovative yet inexpensive targeted therapies for both high-income and low-/middle-income countries.
    .

• Growth Attenuation of Cutaneous Angiosarcoma With Propranolol-Mediated β-Blockade http://archderm.jamanetwork.com/article.aspx?articleid=2436318
  Our data suggest that β-blockade alone substantially reduced angiosarcoma proliferation and, in combination with standard therapy, is effective for reducing the size of the tumor and preventing metastases. If successful, β-blockade could be the first major advancement in the treatment of angiosarcoma in decades.

Mechanism:

Three different β-adrenergic receptor (AR) subtypes are known definitively to exist: β1, β2, and β3. These β-ARs are G-protein-coupled receptors and are present on endothelial cells. When β1 and β2-ARs are activated, they cause vasodilation of peripheral vessels, with β2 receptors predominating in most vascular smooth muscle, except for the coronary and cerebral arteries, where β1 receptors predominate. The β3 receptor is also identified in blood vessels as a mediator of vasodilation.

Mechanistically, when activated, the receptors promote intracellular signal transduction pathways through the downstream activation of cyclic adenosine monophosphate (cAMP), and hence the activation of cAMP-dependent protein kinase A (PKA). The activation of PKA leads to activation of endothelial NO synthase (eNOS), releasing nitric oxide and causing vasodilation. In addition, activation of β-ARs results in the synthesis of proangiogenic factors, such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), which activate proangiogenic cascades [extracellular signal-related kinases/mitogen-activated protein kinases (MAPK) cascade] promoting angiogenesis. Also, activation of β-ARs inhibits apoptosis mediated by Src tyrosine kinase, MAPK, and caspase cascades.

PKA can phosphorylate β1 and β2-ARs, resulting in uncoupling and internalization. Dephosphorylation ensues, followed by recycling of the receptor to the cell membrane. Phosphorylation and internalization leads to desensitization. The β3-AR is resistant to this desensitization. (Ref.)

Propranolol is a β1- and β2-receptor antagonist leading to

• vasoconstriction,
• inhibition of angiogenesis,
• induction of apoptosis and
• inhibition of metastasis (Ref1., Ref.2)
• inhibits stress-induced LDHA activation and COX2 (see discussion above)

It can also reduce or inhibit hexokinase-2 (HK-2)  and thus reduce glucose metabolism, an anti cancer mechanism similar to one of the main mechanisms behind 3 Bromopyruvate (3-BP) http://www.ncbi.nlm.nih.gov/pubmed/24504055 This anti cancer mechanisms makes Propranolol relevant for most types of cancers.

Recently (2018) Propranolol has been found to have autophagy inhibition properties (Ref.).

Administration & Dose:

Oral administration: starting with 40 mg twice a day, and after a week going to 40 mg 3x/day (Ref.)

Due to the reasons discussed here (Ref.) it is best to take the drug at about 6:00am and/or 17:00 pm.

Details on why the timing above would be best:
– Main target of Propranolol ADRB1 and ADRB2 (for reference see mechanism section above)
– Expresion of ADRB1 is at 19:00 and that of ADRB2 is at 08:00 hours http://www.freepatentsonline.com/y2018/0071272.html
– Half life: 4hours https://www.drugbank.ca/drugs/DB00571

Safety & Toxicity:

Propranolol has few side effects http://www.gammaaminobutyricacid.org/beta-blockers-for-anxiety/

http://www.nhs.uk/conditions/Beta-blockers/Pages/Side-effects.aspx

Those who take Propranolol daily should not suddenly stop; it must be slowly eased off or else it is very likely the patient will suffer withdrawal symptoms http://www.gammaaminobutyricacid.org/beta-blockers-for-anxiety/

The most serious aspect that should be taken into account in my opinion is the impact of the beta blockers on the heart rate. If there are already issues related to reduced heart rate or blood pressure I with strongly reconsider the administration of the drug.

Source:

Local pharmacy (on prescription) or online pharmacy, e.g. http://www.buy-pharma.co/Generic-Inderal-Propranolol-Tablet-p-207.html

References:

β-Adrenergic system, a backstage manipulator regulating tumour progression and drug target in cancer therapy http://www.sciencedirect.com/science/article/pii/S1044579X13000850

β-Adrenoceptors are broadly distributed in various tissues of the body. Stress hormones regulate a panel of important physiological functions and disease states including cancer. Nicotine and its derivatives could stimulate the release of stress hormones from cancer cells, leading to the promotion of cancer development. β-Blockers have been widely used to control hypertension for decades. Recently, these agents could have significant implications in cancer therapy through blockade of adrenoceptors in tumour tissues. In this review, we summarize recent advancements about the influence of stress hormones, nicotine and β-adrenoceptors on cancer cell proliferation, apoptosis, invasion and metastasis, and also tumour vasculature normalization. Relevant signal pathways and potential value of β-blockers in the treatment of cancer are also discussed in this review.

β-blockers increase response to chemotherapy via direct antitumour and anti-angiogenic mechanisms in neuroblastoma http://www.nature.com/bjc/journal/v108/n12/full/bjc2013205a.html

background: The use of β-blockers for the management of hypertension has been recently associated with significant clinical benefits in cancer patients. Herein, we investigated whether β-blockers could be used in combination with chemotherapy for the treatment of neuroblastoma.
methods: Seven β-blockers were tested for their antiproliferative and anti-angiogenic properties alone, and in combination with chemotherapy in vitro; the most potent drug combinations were evaluated in vivo in the TH-MYCN mouse model of neuroblastoma.
results: Three β-blockers (i.e., carvedilol, nebivolol and propranolol) exhibited potent anticancer properties in vitro and interacted synergistically with vincristine, independently of P-glycoprotein expression. β-blockers potentiated the anti-angiogenic, antimitochondrial, antimitotic and ultimately pro-apoptotic effects of vincristine. In vivo, β-blockers alone transiently slowed tumour growth as compared with vehicle only (P<0.01). More importantly, when used in combination, β-blockers significantly increased the tumour regression induced by vincristine (P<0.05). This effect was associated with an increase in tumour angiogenesis inhibition (P<0.001) and ultimately resulted in a four-fold increase in median survival, as compared with vincristine alone (P<0.01).
conclusion: β-blockers can increase treatment efficacy against neuroblastoma, and their combination with chemotherapy may prove beneficial for the treatment of this disease and other drug-refractory cancers.

Propranolol potentiates the anti-angiogenic effects and anti-tumor efficacy of chemotherapy agents: implication in breast cancer treatment http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=343

Disclaimer:

This site is not designed to and does not provide medical advice, professional diagnosis, opinion, treatment or services to you or to any other individual. Through this site and linkages to other sites, I provide general information for educational purposes only. The information provided in this site, or through linkages to other sites, is not a substitute for medical or professional care, and you should not use the information in place of a visit, call consultation or the advice of your physician or other healthcare provider. I am not liable or responsible for any advice, course of treatment, diagnosis or any other information, services or product you obtain through this site. This is just my own personal opinion regarding what we have learned on this road.

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